title: The autism candidate gene Neurobeachin encodes a scaffolding protein implicated in membrane trafficking and signaling.
abstract: Autism is a developmental disorder of the central nervous system characterized by impairments in social interaction, communication and restricted repetitive and stereotyped behavior. It is generally assumed that in most cases autism has a polygenic cause, but the pathogenesis is still unknown. Neurobeachin (NBEA) has recently been identified as a candidate gene for autism in a patient with a de novo chromosomal translocation and three patients with a monoallelic deletion. This multidomain scaffolding protein has been suggested to be involved in neuronal post-Golgi membrane traffic. Knockout of Nbea in two independent mouse models has demonstrated a role in neurotransmitter release and synaptic functioning. Knockdown in a cell line has shown a role as negative regulator of secretion of large dense-core vesicles (LDCVs) and haploinsufficiency in blood platelets results in dense granules with an aberrant morphology. A potential role in vesicle transport is further supported by a study of SEL-2, the C.elegans homologue of NBEA. This protein was identified as a negative regulator of LIN-12/Notch activity, probably due to defects in endosomal trafficking. Members of the Notch pathway have also been shown to be modifiers of the NBEA homologue in Drosophila, rugose. These new insights in the function of NBEA may help identifying novel pathways affected in autistic patients. In particular, it suggests that impaired functionality of LDCVs, which contain neurotrophins, neuropeptides and monoamines, might contribute to the pathogenesis of autism in at least a subgroup of patients.
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, and Leuven Autism Research Consortium (LAuRes), Katholieke Universiteit Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Volders
authors.forename: K
authors.initials: K
authors.lastname: Nuytens
authors.forename: J W M
authors.initials: JW
authors.lastname: Creemers
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D029721:Drosophila Proteins; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; C498595:NBEA protein, human; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D051880:Receptors, Notch; C519905:SEL-2 protein, C elegans; C108769:rg protein, Drosophila